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3,5,7-Substituted Pyrazolo[4,3‑<i>d</i>]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models
Abstract
Cyclin-dependent kinases are therapeutic targets frequently deregulated in various cancers. By convenient alkylation of the 5-sulfanyl group, we synthesized 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with various substitutions at position 5 with potent antiproliferative activity in non-Hodgkin lymphoma cell lines. The most potent derivative 4.35 also displayed activities across more than 60 cancer cell lines. The kinase profiling confirmed high selectivity of 4.35 toward cyclin-dependent kinases (CDKs) 2, 5, and 9, and the cocrystal with CDK2/cyclin A2 revealed its binding in the active site. Cultured lymphoma cell lines treated with 4.35 showed dephosphorylation of CDK substrates, cleavage of PARP-1, downregulation of XIAP and MCL-1, and activation of caspases, which collectively confirmed ongoing apoptosis. Moreover, 4.35 demonstrated significant activity in various cell line xenograft and patient-derived xenograft mouse models in vivo both as a monotherapy and as a combination therapy with the BCL2-targeting venetoclax. These findings support further studies of combinatorial treatment based on CDK inhibitors- Text
- Journal contribution
- Biochemistry
- Cell Biology
- Genetics
- Molecular Biology
- Pharmacology
- Biotechnology
- Evolutionary Biology
- Cancer
- Mental Health
- Infectious Diseases
- Virology
- Computational Biology
- Chemical Sciences not elsewhere classified
- PARP
- BCL 2-targeting venetoclax
- 4.35
- pyrimidine Inhibitors
- antiproliferative activity
- findings support
- 60 cancer cell lines
- cyclin-dependent kinases
- combinatorial treatment
- non-Hodgkin lymphoma cell lines
- Lymphoma Models Cyclin-dependent kinases
- XIAP
- Cultured lymphoma cell lines
- CDK inhibitors
- CDK substrates
- position 5
- Cyclin-Dependent Kinases
- 5- sulfanyl group
- combination therapy
- cell line xenograft
- patient-derived xenograft mouse models
- MCL